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Volume 17, Number 9,
Issue of May 1, 1997
pp. 3064-3073
Copyright ©1997 Society for Neuroscience
Mechanisms of Cell Death Induced by the Mitochondrial Toxin
3-Nitropropionic Acid: Acute Excitotoxic Necrosis and Delayed
Apoptosis
Received Nov. 13, 1996; revised Feb. 13, 1997; accepted Feb. 17, 1997.
Zhen Pang and
James W. Geddes
Sanders-Brown Center on Aging and Department of Anatomy and
Neurobiology, University of Kentucky, Lexington, Kentucky 40536-0230
Impaired energy metabolism may play an important role in
neuronal cell death after brain ischemia and in late-onset
neurodegenerative diseases. Both excitotoxic necrosis and apoptosis
have been implicated in cell death induced by metabolic impairment.
However, the factors that determine whether cells undergo apoptosis or
necrosis are not known. In the present study, metabolic impairment was
induced by 3-nitropropionic acid (3-NP), a suicide inhibitor of
succinate dehydrogenase. Treatment of cultured rat hippocampal
neurons with 3-NP resulted in two types of cell death with
distinct morphological, pharmacological, and biochemical features. A
rapid necrotic cell death, characterized by cell swelling and nuclear
shrinkage, could be completely prevented by the NMDA receptor
antagonist MK-801 (10 µM) and dose-dependently
potentiated by low micromolar levels of extracellular glutamate. A
slowly evolving apoptotic death, characterized by nuclear
fragmentation, was not attenuated by MK-801 but was prevented by
cycloheximide (1 µg/ml). The combination of MK-801 and cycloheximide
resulted in an almost complete protection against 3-NP-induced cell
death. DNA fragmentation, detected by the terminal
deoxynucleotidyl transferase-mediated dUTP-X 3 nick end-labeling
technique, was a late event in apoptosis and also occurred after
necrotic cell death. ATP depletion was an early event in the
3-NP-induced neuronal degeneration, and the decline in ATP was
exacerbated by glutamate. We conclude that 3-NP triggers two separate
cell death pathways: an excitotoxic necrosis as a result of NMDA
receptor activation and a delayed apoptosis that is NMDA
receptor-independent. Mildly elevated levels of extracellular glutamate
shift the cell death mechanism from apoptosis to necrosis.
Key words:
energy metabolism;
succinate dehydrogenase;
3-nitropropionic acid;
excitotoxicity;
apoptosis;
necrosis;
nuclear
fragmentation;
TUNEL;
ATP
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